Project Summary The development of a mathematical model is critical to the understanding of complex biological pro- cesses because it codi es current understanding so that it can be tested against existing data. A good model with sucient detail can be used to identify potential points of intervention (for example, drug targets) at which an undesired outcome (for example, e ects of disease) of the process might be altered. Model develop- ment proceeds through a cycle of model building, simulation of the model under numerous conditions, and comparison to experimental data. The cycle is repeated and often augmented by new experiments to capture additional data, until the resulting model can plausibly explain the data. Tremendous amounts of time and e ort must be devoted to nding and/or developing tools to analyze the model and compare it to the data, t the parameters and assess the e ects of typically large amounts of uncertainty in both the data and the parameters, simulate the model and analyze the simulation data, re ne the model to better capture our increased understanding at each stage of the process, decide which additional experiments would add most to our understanding, etc. Our objective in the proposed work is to facilitate and accelerate the modeling process by providing state of the art, well-integrated tools to report complete and informative results at each stage, enabling the modeler and the experimentalist to focus on what they do best: scienti c discovery. This is a renewal proposal that builds on the capabilities and infrastructure developed in the current project. In that work we developed StochSS, a novel Software-as-a-Service o ering for quantitative modeling of biochemical networks capable of seamless deployment in public cloud environments. StochSS does an excellent job of supporting two of the major steps of the modeling process: Model Building { taking your model description and putting it into a form that the StochSS simulation engines can work with, and Simulation { performing the simulations to produce the results. The proposed project has three complementary Aims. The rst is to further develop StochSS's core capabilities and to take the steps that will ensure its long-term sustainability; the second is to develop a Model Development Toolkit, and the third is to develop a Model Exploration Toolkit. Both of these toolkits will be integrated into our existing StochSS Model Building and Simulation environment and will leverage our existing software infrastructure for cloud computing. Aim 1. Core Capabilities and Long-Term Sustainability This aim has three sub-aims: (1) instituting practices that will help ensure community involvement and better long-term sustainability of StochSS beyond NIH funding, (2) extending core StochSS functional capabilities, and (3) improving compatibility with other software via support for standard data formats. Aim 2. Model Development Toolkit Develop and integrate tools to facilitate and accelerate the process of Model Development: the iterations of (modeling, simulation, experiment) that are typically required to converge on the most plausible model that can explain the data. The Model Development Toolkit will address parameter estimation and quanti cation of uncertainty, generation and evaluation of the set of plausible models, and optimal design of experiments. Aim 3. Model Exploration Toolkit Develop and integrate tools for Model Exploration: the process of exploring the parameter space to ensure that the model is robust to variations in uncertain and/or undetermined parameters, to nd the regions of parameter space in which the model is capable of yielding a given behavior, and to discover all of the qualitatively distinct behaviors that the model is capable of within the space of uncertain and/or undetermined parameters. 1